The short half lives of the radioisotopes used for PET radiochemistry require that radiosyntheses are currently carried out rapidly and efficiently. Radiosyntheses and isolation of radiolabelled products are carried out using automated systems which are contained in large lead shielded “hot cells” to prevent radiation exposure to the operator. Such systems typically handle liquid volumes in the range 0.2 to 0.5 milliliters, though the number of radioactive atoms or molecules present is extremely small, typically 6.23×1011 atoms or molecules. The current approach to automation of radiosyntheses is limited in flexibility and capacity and is also space consuming. There is also a need for automated radiosynthesis systems which are smaller, simpler, more flexible, multi-tasking, and with greater throughput capacity.
The radiosynthesis of radiotracers for PET involves several steps ranging from radioisotope production, incorporation of radioisotopes into suitable radiolabelling agents, radiolabelling of precursors, purification of radiolabelled products, and quality control analysis. Despite these many steps, the short half-lives of the radioisotopes used, require that the radiosynthesis is carried out rapidly and efficiently.
We now propose that performing radiochemistry on microfabricated devices will allow miniaturisation of automated radiosynthesis systems, or components thereof and hence may solve some of these problems. A major advantage of the proposed technology is that it will provide a generic system for performing radiochemistry with any isotope, for example, carbon-11 or fluorine-18. This approach may also allow simplification of automated synthesis systems, increased radiochemical yield and specific radioactivity of products because of shorter and more efficient reactions and more rapid isolation and analysis, and higher throughput because of the use of mass-produced disposable components.
Microreactors used for biochemical reactions have generally concentrated on developing continuous flow polymerase chain reactions (PCR) on a chip coupled with DNA sequencing using capilliary electrophoresis (CE), and microchip devices for performing enzyme assays. Until relatively recently, microfabrication research has concentrated on developing analytical microstructures rather than chemical synthesis microstructures. Reviews of methods for construction of microfabricated devices and their application inter alia in synthetic chemistry, may be found in DeWitt, (1999) “Microreactors for Chemical Synthesis”, Current Opinion in Chemical Biology, 3:350-6; Haswell, Middleton et al (2001) “The Application of Microreactors to Synthetic Chemistry”, Chemical Communications: 391-8; Haswell and Skelton (2000) “Chemical and Biochemical Microreactors”, Trends in Analytical Chemistry 19(6), 389-395; and Jensen (2001) “Microreaction Engineering—Is Small Better?” Chemical Engineering Science, 56:293-303.